Investigators Seek Markers for Sensitivity to EGFR Inhibitors

Investigators Seek Markers for Sensitivity to EGFR Inhibitors

NEW YORK-The drive to find
markers that will predict which patients
will benefit from erlotinib
(Tarceva) and gefitinib (Iressa) inched
forward with studies reported from
two groups at the 40th annual meeting
of the American Society of Clinical
Oncology. Both studies used human
non-small-cell lung cancer
(NSCLC) cell lines to identify panels
of markers that not only provide the
basis for development of clinically useful
screening tests for erlotinib and
gefitinib sensitivity, but also open new
possibilities for overcoming resistance
to these agents.
Roman Perez-Soler, MD, of
Montefiore Medical Center, New
York, and colleagues reported that in
a panel of nine human NSCLC cell
lines, two were highly sensitive to
erlotinib (Tarceva) and both expressed
epidermal growth factor receptor
(EGFR). The other seven cell
lines were resistant, but five of them
expressed EGFR (abstract 7026).
Erlotinib induced G1-S phase arrest
in sensitive cells and to some extent
in resistant cells. Sensitivity to
erlotinib did not correlate with expression
of ErbB family genes, nor
was there any correlation between
drug sensitivity and baseline p-HER1
or EGFR expression.
There were no differences in
baseline expression of P-EGFR between
sensitive and resistant cell lines.
Baseline expression of P-ERK1/2,
P-AKT, and P-STAT-3 was undetectable
or low in sensitive cell lines but
high in most resistant cell lines.
Erlotinib resistance correlated
with higher baseline expression of
p-MAPK, p-Akt, and p-STAT. Induction
of p-HER1/EGFR and p-AKT by
EGF was seen in both sensitive and
resistant cells and was blocked by
erlotinib in both groups.
"These data support the hypothesis
that HER1/EGFR-independent
baseline activation of downstream signaling
molecules may define the patient
subpopulation less likely to derive
clinical benefit from erlotinib
therapy," Dr. Perez-Soler said.
The investigators analyzed effects of erlotinib on the cell cycle by flow
cytometry. They measured expression
of the activated upstream and downstream
elements of the EGFR pathway
(EGFR, ERK1/2, AKT, and STAT-
3) at baseline and after stimulation
with EGF, determined by western blot
analysis.
Second Study
In the second study, investigator
Fred R. Hirsch, MD, of the University
of Colorado Health Sciences Center
in Denver reported gene array data
showing that E-cadherin signaling
plays a central role in determining
gefitinib sensitivity (abstract 7015).
High expression of E-cadherin correlated
with high sensitivity to gefitinib
and that high expression of SIP-1 and
ZEB-1 correlated with high resistance
to gefitinib.
Dr. Hirsch and colleagues determined
gefitinib sensitivity in 18
NSCLC cell lines. Ten cells lines were
studied using oligonucleotide
microarray analysis. The researchers
used three distinct filtration and normalization
algorithms to process the
expression data and generate a list of
144 candidate genes. This approach
was combined with five machinelearning
algorithms to build a test set
for predictor genes. The 16 genes
whose expression was more than
threefold different in sensitive vs resistant cells were verified by quantitative
real-time reverse transcriptase
polymerase chain reaction (RT-PCR).
The final analysis identified a panel
of 13 different genes that were able
to predict gefitinib in 9 of 10 cell lines
used for validation. "This biomarker
panel may be of significant value for
selecting NSCLC patients for gefitinib
treatment," Dr. Hirsch said.
Future Study
Directions
According to Dr. Hirsch, future
directions for this research will include
confirming the predictive value of Ecadherin,
HER3, SIP-1, and ZEB-1
expression in a test set of cell lines and
identifying genes in the microarray
gene set that are controlled by SIP-1
and ZEB-1.
Early work has already shown that
five markers from this set predicted
gefitinib sensitivity in 9 of 10 cell lines
tested. "We will also continue attempts
to overcome resistance, by blocking
ZEB-1 and SIP-1," he said.
The researchers have attempted to
do this by using histone deacetylase
inhibitors but they were unsuccessful.
They will be trying sRNA constructs
next. A prospective trial evaluating
the relationship of expression of
SIP-1, ZEB-1, E-cadherin, and HER3
to EGFR mutations is being planned
investigators noted.

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